dermatlogy

1. Disorders of pigmentation
Presenter – Dr. Eyasu (R1)
Moderator- Dr. Hadas (Pathologist)
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2. Outline
• Introduction
• Disorders characterized by hypopigmentation
• Disorders characterized by hyperpigmentation
• References
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3. Introduction
• Melanocytes are found along the dermal-epidermal
junction as well as within hair follicles.
• Responsible for the production and secretion of
melanin pigment.
• Characterized by small, dark, ovoid nuclei and scant,
clear cytoplasm.
• They number from one per 10 to one per five basal
keratinocytes, with higher concentrations on the face
and genitalia.
• Pigment is not normally visible in their cytoplasms
because it is rapidly secreted and taken up by basal
keratinocytes, where it is stored and gradually broken
down.
• Although the amount of melanin produced and stored
varies between darker and lighter skinned individuals,
the number of melanocytes does not.
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Melanocytes

4. Introduction…
• The pigmentary system involves a complex set of reactions with numerous potential sites for
dysfunction.
• Melanin is produced in melanosomes in the cytoplasm of melanocytes by the action of tyrosinase
on tyrosine.
• The melanin synthesized in any one melanocyte is then transferred to an average of 36
keratinocytes.
1) Through the phagocytosis of the melanin-laden dendritic tips of the melanocytes.
2) Exocytosis of melanocores (polymerized melanin) followed by release into the extracellular
space and ingestion by adjacent keratinocytes.
• Any inflammatory process involving the epidermal basilar layer that can disrupt this transfer of
melanin as well as specific enzyme defects and destruction of melanocytes may result in
hypopigmentation.
• The pathogenesis of hyperpigmentation is not as well understood.
• Prominent pigment incontinence and increase in size or melanization of the melanosomes are
possible mechanisms.
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5. Introduction…
• This seminar deals with the various disorders of cutaneous
pigmentation, excluding those entities in which there is an obvious
lentiginous proliferation of melanocytes and tumors of the nevus
cell–melanocyte system.
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6. 1. Disorders Characterized By
Hypopigmentation
• Categories on the basis of their presumed pathogenesis.
1) Abnormal migration/differentiation of melanoblasts: piebaldism,
Waardenburg’s and Woolf ’s syndromes
2) Destruction of melanocytes: vitiligo, chemical leukoderma
3) Reduced tyrosinase activity: oculocutaneous albinism type 1A
4) Abnormal structure of melanosomes: “ash leaf spots”, Chédiak–Higashi
syndrome, progressive macular hypomelanosis
5) Reduced melanization and/or numbers of melanosomes: albinism, Griscelli
syndrome, idiopathic guttate hypomelanosis, hypomelanosis of Ito, “ash leaf
spots,” pityriasis versicolor, nevus depigmentosus
6) Reduced transfer to keratinocytes: nevus depigmentosus, pityriasis alba,
postinflammatory leukoderma, pityriasis versicolor, Chédiak–Higashi syndrome
7) Abnormal vasculature: nevus anemicus
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7. 1.1. Vitiligo
• A common acquired disease of unknown etiology characterized by selective loss
of melanocytes.
• Incidence- between 1% and 2% of the population.
• More common in people with dark skin.
• The sex incidence is equal, with a peak age between 10 and 30 years (up to 50%
of cases).
• Between 25% and 40% of patients have a positive family history of the disease
• Almost 15% of late-onset cases demonstrate the Koebner phenomenon.
• Approximately 20% to 30% of patients have an associated autoimmune and/or
endocrine disorder such as Hashimoto’s disease, hyperthyroidism, pernicious
anemia, Addison’s disease, type 1 diabetes mellitus, and alopecia areata.
• Childhood-onset vitiligo: female predominance, may show eyelid involvement as
the initial site, less common mucosal involvement.
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8. 1.1. Vitiligo…
• Results in symmetrical macular areas of leukoderma that
progressively enlarge and often become confluent.
• There is a predilection for the face, back of the hands,
axillae, groins, umbilicus, and genitalia and for the skin
overlying bony areas such as the knees and elbows.
• Vitiligo has been reported on the anterior neck in Muslim
women.
• It is thought to be due to the Koebner phenomenon
resulting from the wearing of scarves that are tied with
metallic or plastic pins in this region.
• Sometimes the depigmented area is segmental or
dermatomal in distribution (type B); more often, it is
more generalized (type A).
• Mucous membrane involvement with vitiligo can involve
the lips, gingiva and anogenital region.
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9. 1.1. Vitiligo…
• Some drugs and other agents are reported to produce
depigmentation resembling vitiligo: chloroquine, imatinib,
zidovudine, lamivudine, efavirenz…
• Vitiliginous skin is generally resistant to developing dermatitis in
response to contact allergens, and it also has the remarkable property
of resistance to forming nonmelanoma skin cancers, in contrast to the
depigmented skin of albinos.
• Vitiligo may be a presenting sign of metastatic melanoma- patients
have a better prognosis than those who do not develop vitiligo-like
depigmentation .
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10. 1.1. Vitiligo…
• Pathogenesis- three hypotheses
• Neurogenic hypothesis - production of a neurochemical mediator by
the nerve endings in the skin, leading to inhibition of melanogenesis
and destruction of melanocytes.
• Self-destruction theory - proposes that melanocytes are destroyed by
toxic melanin precursors such as free radicals. Experimental evidence
is based on the fact that a number of chemicals induce pigmentary
changes indistinguishable from vitiligo.
• Autoimmune hypothesis - based on the observation that patients with
vitiligo have an associated autoimmune disease in up to between 15–
30% of cases.
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11. 1.1. Vitiligo…
• Histological features
• complete absence of melanocytes in association
with total loss of epidermal pigmentation.
• Biopsies from the periphery of lesions with a
clinically inflammatory border show lymphocytes
and histiocytes in the papillary dermis.
• Some inflammatory cells may also be found at the
periphery, even in the absence of a clinically
inflamed border.
• At the advancing border, the melanocytes may be
increased in size with an increased number of
dendrites.
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S-100 protein

12. 1.1. Vitiligo…
• Differential diagnosis
• Guttate hypomelanosis- clinical presentation and the complete
absence of melanocytes in vitiligo, and the persistence of at least
some melanocytes in the former.
• Post inflammatory hypopigmentation- preservation of melanocytes
with only loss of pigment.
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13. 1.2. Oculocutaneous Albinism
• A genetically heterogeneous group of disorders in which there is a
generalized decrease or absence of melanin pigment in the eyes, hair, and
skin.
• At least 10 forms of this condition have been identified, each presumably
resulting from a different biochemical block in the synthesis of melanin.
• The most common forms are types 1 and 2, which account for 40% and
50%, respectively, of cases worldwide.
• Type 1A is due to complete absence of tyrosinase activity in melanocytes
whereas in type 1B there is reduced activity of tyrosinase.
• Oculocutaneous albinism type 2 is caused by mutations in the gene OCa2.
The OCa2 protein is important in the formation of melanosomes and in
transport of melanosomal proteins.
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14. 1.2. Oculocutaneous Albinism…
• The clinical manifestations of oculocutaneous
albinism depend on the type of biochemical
abnormality.
• In all types of albinism, the lack of melanin in the
developing eye results in hypoplasia of the fovea
and abnormal routing of the optic nerves.
• As a result, all patients have variable strabismus,
nystagmus, and reduced visual acuity.
• Affected patients often have an increased risk of
skin cancer.
• Based on clinical features alone, it is not always
possible to separate the different types of
oculocutaneous albinism.
• The clinical presentation at birth is white hair and
skin and blue eyes.
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15. 1.2. Oculocutaneous Albinism…
• Histological features
• Reduced or complete absence of
melanin in the epidermis and hair
follicles, depending on the type of
oculocutaneous albinism.
• Melanocytes are normal in number and
morphology.
• Tyrosinase activity is lacking in
melanocytes in freshly plucked anagen
hair bulbs in type 1A; it is reduced in
heterozygotes with this phenotype and
variably reduced in some of the other
types.
• Tyrosinase activity is normal in type 2.
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16. 1.3. Tuberous Sclerosis: Hypopigmented
Macules (“Ash Leaf Spots”)
• Tuberous sclerosis is characterized by the
triad of epilepsy, mental retardation, and
multiple angiofibromas.
• In addition, circumscribed macules of
hypopigmentation known as “ash leaf
spots” can be present at birth on the
trunk and lower extremities.
• The basic abnormality appears to be an
arrest in the maturation of melanosomes.
• They vary in diameter from 1 mm to 12
cm.
• The more common shapes are oval,
polygonal, or ash leaf–like.
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17. 1.3. Tuberous Sclerosis: Hypopigmented
Macules (“Ash Leaf Spots”)…
• Histopathology
• Numbers of melanocytes are not
decreased in the hypopigmented
macules, which can be confirmed
with melan-A staining.
• Epidermal melanin is reduced but
not absent.
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18. 1.4. Piebaldism
• A rare congenital disorder inherited in an autosomal
dominant manner.
• There are nonprogressive, discrete patches of
leukoderma.
• The central area of the forehead, the anterior trunk,
and the mid areas of the extremities are
characteristically affected.
• The hands, feet, and back are usually spared.
• In 90% of cases there is a white forelock in the frontal
mid scalp; this may be the only manifestation of the
disease.
• Café-au-lait spots are a frequent finding. An
association with neurofibromatosis type 1 has been
documented.
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19. 1.4. Piebaldism…
• Histological features
• complete absence of melanocytes
• Abnormal melanocytes may be seen in areas of transition between
involved and normal skin.
• These melanocytes may have spherical melanosomes.
• Some clear cells, representing Langerhans cells, are usually present in
the epidermis.
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20. 1.5. Pityriasis Alba
• One of the most common localized
disorders of hypopigmentation in
children.
• Young adults may also be affected.
• Slightly more common in dark-skinned
atopic males.
• Ill-defined, slightly scaly patches of
hypopigmentation on the face with
predilection for the cheeks.
• Also seen on the neck and shoulders.
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21. 1.5. Pityriasis Alba…
• Histologically, the changes are
often subtle and consist of mild
hyperkeratosis, focal parakeratosis,
minimal spongiosis, and variable
exocytosis of lymphocytes.
• This is associated with mild loss of
melanin in basal keratinocytes but
not in the number of melanocytes.
• In the dermis there is mild pigment
incontinence and a sparse
superficial, perivascular
lymphohistiocytic inflammatory
cell infiltrate.
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22. 1.6. Idiopathic Guttate Hypomelanosis
• a common leukodermic
dermatosis of unknown cause.
• Multiple hypochromic macules,
2 to 5 mm in diameter which
develop over many years.
• Usually found on the sun-
exposed extremities of elderly
individuals.
• Repigmentation does not occur.
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23. 1.6. Idiopathic Guttate Hypomelanosis…
• Variable loss of melanin granules in
epidermal keratinocytes. This is
sometimes associated with epidermal
atrophy and flattening of the rete ridges.
• Orthokeratotic hyperkeratosis in a
basket-weave pattern has also been
documented.
• However, complete loss of melanocytes
is not a feature.
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24. 1.6. Idiopathic Guttate Hypomelanosis…
• DDx- lichen sclerosus, hypopigmented mycosis fungoides, atrophie
blanche, vitiligo, pityriasis versicolor, leprosy, and the hypopigmented
lesions seen in tuberous sclerosis.
• Most of these entities are easy to exclude histologically except for
vitiligo.
• In the latter there is complete absence of melanocytes and this can
be confirmed with a melanocyte-specific immunostain such as Melan-
a, since S-100 also stains Langerhans cells.
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25. 1.7. Postinflammatory Hypopigmentation
• Inflammation of the skin can result in
hyperpigmentation or
hypopigmentation.
• Postinflammatory hypopigmentation is
a very common form of
hypopigmentation.
• The lack of pigment becomes
noticeable as the primary lesion fades.
• The lesion is usually a macule with
indistinct borders and a variable
degree of hypopigmentation.
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26. 1.7. Postinflammatory Hypopigmentation…
• Histologically, there is focal reduction in pigmentation in the basal cell layer
of the epidermis.
• Residual features of the preceding or concurrent inflammatory dermatosis
may also be present.
• The diagnosis is usually obvious by the patient’s report of a previous
inflammatory lesion at the sites of hypopigmentation.
• When no such history can be obtained, the differential diagnosis includes
halo nevus, pityriasis alba, pityriasis versicolor, and cutaneous infections
such as those resulting from Candida spp. or dermatophytes.
• Careful histopathologic examination for the presence of nevus cells and
microorganisms should aid in distinguishing postinflammatory
hypopigmentation from halo nevus and infectious processes, respectively.
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27. 2. Disorders Characterized By
Hyperpigmentation
• The following subclassification provides a useful approach to a biopsy from
hyperpigmented lesions:
1. Disorders with basal hyperpigmentation: melasma, acquired brachial
dyschromatosis, ephelis (freckle), café-au-lait spots, macules of Albright’s
syndrome, Laugier–Hunziker syndrome, Peutz–Jeghers syndrome, and Becker’s
nevus (melanosis)…
2. Disorders with epidermal changes: Dowling–Degos disease, Kitamura’s
disease, and confluent and reticulated papillomatosis of Gougerot–Carteaud…
3. Disorders with striking melanin incontinence: postinflammatory melanosis,
prurigo pigmentosa, generalized melanosis in malignant melanoma…
4. Disorders with melanin incontinence and epidermal atrophy or “dyskeratotic”
cells: dyskeratosis congenita, frictional melanosis, active fixed drug eruptions,
and active prurigo pigmentosa…
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28. 2.1. Melasma (chloasma)
• An acquired, chronic, recurrent lesion that develops
in some women, especially those living in areas of
intense UV radiation, who are pregnant or taking
oral contraceptives.
• Its incidence in pregnancy varies from 15% to 50%.
• An association has also been documented with
cosmetics, phototoxic drugs, isotretinoin, and
anticonvulsants.
• Melasma also occurs, though less commonly, in
men.
• There is a marked predilection for the face
(forehead and cheeks).
• Symmetrical hyperpigmentation characterized by
irregular light to dark-brown confluent or speckled
macules with sharply demarcated margins involving
sun-exposed skin.
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29. 2.1. Melasma…
• Histologically, there is increased melanin in the
epidermis, particularly in the basal layers.
• Melanin pigment is located in a “cap” overlying the
keratinocyte nuclei.
• Normal melanocyte numbers in all cases.
• However, melanocytes are enlarged and have
increased numbers of dendrites.
• Mild pigment incontinence is sometimes present,
along with a perivascular lymphohistiocytic infiltrate
and increased vascularity.
• Solar elastosis is more prominent than in normal
skin.
• Mast cells are also increased in number.
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30. 2.2. Cafe´-au-lait spots
• “coffee-with-milk”
• They may be present at birth or develop within the first few
years of life.
• They are found in approximately 15% of individuals.
• They are not increased in patients with tuberous sclerosis.
• Multiple café-au-lait spots are a feature of
neurofibromatosis (95% of NF1 patients). Axillary freckling is
often also present in these cases.
• Café-au-lait spots have also been reported in Bloom’s
syndrome, Cowden’s disease, Fanconi’s anemia, ring
chromosome syndromes, ataxia–telangiectasia, nevoid BCC
syndrome, Legius syndrome, and Noonan’s syndrome.
• Uniformly pigmented, tan to dark brown macules with well-
defined borders that vary in size from small, freckle-like
lesions to large patches 20 cm or more in diameter.
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31. 2.2. Cafe´-au-lait spots…
• An increase in melanin pigment deposition
within basilar keratinocytes.
• The density of melanocytes is normal or only
slightly increased.
• The increased pigmentation typically spares
the adnexal epithelium.
• Giant melanin granules (macromelanosomes)
can be seen in café-au-lait spots in many
patients with neurofibromatosis.
• The diagnostic significance of
macromelanosomes is diminished by their
absence in some children with
neurofibromatosis and their presence in
normal skin and other pigmented macular
lesions.
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32. 2.2. Cafe´-au-lait spots…
• Differential diagnosis
• Postinflammatory hyperpigmentation, melasma, melanocytic nevi.
• Café au-lait macules have a tendency to grow in proportion to growth of the rest
of the body.
• They do not change with sun protection or bleaching agents.
• Their completely macular appearance may be helpful for the correct diagnosis.
• Histologically café-au-lait macules are usually indistinguishable from freckles,
melasma, and the melanotic macules of Albright’s syndrome.
• They can be differentiated from melanocytic nevi and simple lentigines by their
lack of melanocyte proliferation and rete ridge elongation.
• Café-au-lait macules differ from lesions of postinflammatory hyperpigmentation
by the presence of an inflammatory infiltrate or pigment incontinence in the
latter.
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33. 2.3. Ephelis (Freckle)
• Ephelides (freckles) are small,
well-defined, pigmented macules
1 to 2 mm in diameter.
• Show predilection for the face,
arms, and shoulder regions of fair-
skinned individuals.
• They appear at an early age and
may follow an episode of severe
sunburn.
• Darken easily with sun exposure.
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34. 2.3. Ephelis (Freckle)…
• The epidermis appears normal in structure.
• The basal cells in the affected areas are
more heavily pigmented with melanin than
those in the surrounding skin.
• There is usually sharp delimitation of the
abnormal areas from the normal.
• There are normal numbers of melanocytes.
• No elongation of rete ridges and no nests.
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35. 2.4. Macules Of Albright’s Syndrome
• Albright’s syndrome is characterized by the
triad of polyostotic fibrous dysplasia,
sexual precocity—especially in the female,
and pigmented macules.
• These macules are large, often unilateral,
and related to the side of the bone lesions.
• The outline of the macules is very irregular,
in contrast to that of café-au-lait spots.
• They mainly involve the trunk and proximal
lower limbs and less commonly the face
and neck.
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36. 2.4. Macules Of Albright’s Syndrome…
• A skin biopsy from a pigmented macular
lesion resemble freckles, showing
hyperpigmentation of the basal layer.
• Giant melanosomes are sometimes
seen but are not as frequent as in the
café-au-lait spots of neurofibromatosis
type I.
• In the dermis and subcutaneous tissue,
plaque-like osteomas may be seen.
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37. 2.5. Becker’s Nevus (melanosis)
• Is usually found in the region of the shoulder
girdle as unilateral, hyperpigmented areas of
somewhat thickened skin.
• The male-to-female ratio ranges from 4-6 : 1.
• It is more common in young people with fair
skin.
• Occasionally, lesions have been said to follow
severe sunburn.
• Hypertrichosis may develop after the
pigmentation, but is not invariable.
• May be associated with connective tissue nevus,
accessory scrotum, areolar hypoplasia.
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38. 2.5. Becker’s Nevus...
• The epidermal changes are variable, but
usually there is acanthosis and sometimes
mild papillomatous hyperplasia.
• Elongated rete ridges with pointed or flat
tips.
• There is variable hyperpigmentation of the
basal layer with some melanophages in the
dermis.
• Melanocyte proliferation is usually mild and
not always obvious in routine sections;
special studies have shown a quantitative
increase.
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39. 2.6. Postinflammatory Melanosis
• Hyperpigmentation may follow a number of
inflammatory dermatoses, particularly
those involving damage to the basal layer.
• Thus, it may follow various disorders that
present a lichenoid reaction pattern, such
as lichen planus, lichenoid drug eruptions,
and fixed drug eruptions.
• Specific drugs that may cause
postinflammatory and/or increased basal
pigmentation include the following:
prostaglandin analogs, interferon-α,
olanzapine, hydroxyurea, and calcipotriol.
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40. 2.6. Postinflammatory Melanosis…
• There are two major histopathological
types of postinflammatory
hyperpigmentation:
Epidermal- increased basilar epidermal
pigmentation, and
Dermal- marked pigmentation in the upper
dermis and decreased epidermal pigmentation.
• More prominent perivascular lymphocytic
inflammation is seen in the dermal
pigment group.
• Basal pigmentation is prominent in
photodermatitis.
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41. 2.7. Laugier-Hunziker Syndrome
• An acquired disorder characterized by
macular pigmentation of the lips, oral
cavity (mainly hard palate and less
commonly buccal mucosa, soft palate,
and gums) and, less frequently, fingers
and palms.
• Longitudinal melanonychia is seen in up
to 50% of patients.
• Genital and conjunctival pigmentation is
very rare.
• The sex incidence is similar and most
patients are Caucasian and middle aged.
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42. 2.7. Laugier-Hunziker Syndrome…
• Histologically, there is hyperpigmentation of basal keratinocytes and
pigment incontinence with melanophages in the papillary dermis.
• Recently, it has been suggested that there is an increase in the
number of basal dendritic melanocytes and the term ‘mucocutaneous
lentiginosis of Laugier and hunziker’ has been proposed.
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43. References
• Weedon’s Skin Pathology, Fifth Edition
• McKee's Pathology of the Skin, Fourth Edition
• FDP Dermatopathology, Second Edition
• Fitzpatrick’s Dermatology, Ninth Edition
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